A darwinian legacy OR Why we need fluorescent rabbits

My post about fluorescent rabbits is gaining a momentum on the Flickr group 'Bunny Lovers Unite' and in the Rabbitmatch's blog. Most people ask itself: WHY making fluorescent bunnies? And others feel outraged.

Animal research is long debated, and my hope is that the development of new reporter probes would allow to reconsider current research protocols while increasing the scientific significance of the experiments done, this is the focus of my current research. Here, a take opportunity of this little exposure to the non-science world to say why WE CAN make better animal research.

From a modern mechanical and operational perspective, life relies on the interaction between a sworm of molecules and their hierarchical organization into structures in which we distinguish a functional unity (i.e., organelles, cells, tissues, organs and systems). It is current hope and belief that a whole, systematic decoding of such minute, living, interacting building blocks that are bio-molecules, will grant a better comprehension of life mechanisms. From more than one century, we learn how to identify and discriminate those molecules, by means of iterative, multidimensional separation techniques (i.e., 2D electrophoresis, tandem mass spectrometry). This provided us with the awareness of the vast compilation of molecules and their distribution among different single cells and, ultimately, into the whole biome.

Laboratory animals were the main source of specimens to put under our microscopes. However, from the slides, we progressively realized that the picture we were painting was actually a static still-life, without any motion. This is not surprising, given the fact that most of the research conducted so far have been based on post-mortem analyses. Worst, such frozen picture renders difficult to discriminate causes from consequences. Animal sacrifice raises scientific, ethical and economical concerns, moreover the paradox of studying life from dead samples, may reasonably induce to wonder about the artefactual side of the knowledge generated so far. Not only terminal euthanasia, but each animal distress poses the same doubts: are we acquiring a distressed knowledge?

Before the molecular age, giants like Darwin and Mendel revolutionized life sciences with a systematic observation of animal and vegetal living specimen in their natural environment (the galapagos) with minor to null human intervention other than observation. The point is: shall we systematically observe (and understand) molecular life into a living, awake, freely moving animal in its natural environment? Can we imagine a day in which our preferred pet, in the security of our home, would allow to make scientific discoveries because he/she possess a radio-gene able to communicate its physiological and molecular status to our wireless router which will promptly share this information to the scientific community online?

I'm dreaming about normal happy pets, that can be turned into research contributors just through a simple injection. This is science-fiction but we aren't very far from such a goal. Recent advances in molecular imaging led us to dream a clean future for animal research. Take the simplest molecule: H2O. Its diamagnetism led clinicians to monitor water in space and time by means of magnetic resonance imaging (the same can be done for fat). In 2003, we were able to monitor something more elegant than the space-temporal profile of a single molecule in a healthy living mouse: by means of optical bioluminescence imaging, my PhD mentor was able to observe in cycling female mice, not a molecule, but its molecular activity (specifically, the activity of the estrogen receptor, a hormone-regulated transcription factor).

This goal, was achieved by the conceptualization of so-called reporter mice: models engineered in order to allow the external non-invasive monitoring of any selected molecular mechanism in the full respect of animal’s dignity. This is, in other words, the ability to observe the molecular life into a living whole organism. A Darwinian legacy.

The most interesting feature of longitudinal imaging with living animal systems, however, is its excellent potential to Reduce the number of animals because animal sacrifice is NOT needed and each animal is its own control. We need now to improve this technology (toward the radio-gene) to Refine current methods by providing the opportunity to study molecular circuits systematically in 4 dimensions, furthermore new technology will abolish the pain for the animals (and voluntary humans). What we need now, are engineers providing multiplexing abilities and better resolutions (in space and in time). Molecular imaging should be considered a very valid Replacement alternative, and we need to shift mathematical engineers and bioinformaticians from still-life omics data set, to living data set. We need to hope and belief to alternative ways to conduct animal experimentation. Animals aren't humans. We need to develop safer, safest technologies to study gene networks in animals in order to validate the safety and to eventually apply this 'radio-genes' to humans, to ourselves. Nosce te ipsum (know thyself, said Socrates). This blog tales recent advances toward this vision, the vision of a clean, efficient, innocent biomedical research.

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Ciana, P., Raviscioni, M., Mussi, P., Vegeto, E., Que, I., Parker, M., Lowik, C., & Maggi, A. (2003). In vivo imaging of transcriptionally active estrogen receptors Nature Medicine, 9 (1), 82-86 DOI: 10.1038/nm809

Maggi A, & Rando G (2009). Reporter mice for the study of intracellular receptor activity. Methods in molecular biology (Clifton, N.J.), 590, 307-16 PMID: 19763513

Rando G, Biserni A, Ciana P, & Maggi A (2010). Profiling of drug action using reporter mice and molecular imaging. Methods in molecular biology (Clifton, N.J.), 602, 79-92 PMID: 20012393